Amino acids are important chiral sources and act as skeletons in drug discovery. Besides amino and carboxyl groups, some of them bear different functional groups for further modification. Methylation on the terminal hydroxyl group of serine or threonine is an example, and there are several potential agents in the clinic or being approved.
Lacosamide is a typical example of an anti-convulsant agent with a O-methyl-serine skeleton. The same skeleton was also observed in Oprozomib as an anti-cancer drug in the phase II clinical trial. However, the methylation on the terminal hydroxyl group of serine is not very easy. In U.S. Pat. No. 6,048,899, O-methylation was carried out by using silver (I) oxide and iodomethane. However, this process is impractical due to high cost and resulted in around 15% racemisation.
In U.S. Pat. No. 8,809,585, the method described that N-Boc-D-Serine was methylated in the presence of sodium hydroxide in a two-phase system. Chirality increased to 98.1%, but not good enough. On the other hand, HPLC purity was only 96.3%. Although it is claimed in the patent that the chirality was 100% when base changed from sodium hydroxide to n-butyllithium, the purity of product was only 90%. Similar results are also observed in other patents such as WO2012/51551 in which the purity of N-Boc-D-Serine was only higher than 95%.